The disconnect between bone density and fracture susceptibility has spurred the search for other risk factors that cause compromised skeletal strength. The applicants of this proposal previously developed methods, based on quantitative MRI for assessing multiple measures of bone quality, including trabecular bone microstructure via a procedure referred to as virtual bone biopsy (VBB). The potential of this technology has been demonstrated in translational research studies showing that structural measures of bone quality are more strongly associated with osteoporotic fractures than areal BMD and that these structural measures are sensitive indicators of drug intervention efficacy in patients with impaired structural integrity. The critical missing link is the association between measures of structure and measures of strength such as stiffness and failure load. There are very few studies that have attempted to relate in vivo bone- structure derived mechanical estimates from micro-finite element (?FE) analysis, with actual fracture data. Whereas both, high-resolution CT and MRI, are suited for this purpose, MRI has substantial advantages over CT, besides being free of ionizing radiation, in that it has superior bone-to-marrow contrast;and most importantly, an installed base of over 10,000 units in the United States alone. In this project we advance the following hypotheses: 1) that FE-estimated parameters (whole-section stiffness and ultimate strength, and sub-volume trabecular bone elastic and shear moduli) derived from in vivo ?MR images at the distal tibia and radius, are associated with structural parameters expressing scale, topology and orientation at the measurement sites, with structural measures jointly explaining as much as 90% of the variation in the mechanical parameters;2) that these associations are stronger than those involving bone volume fraction or BMD alone;3) that the mechanical and structural parameters at the surrogate sites are correlated with vertebral structural and mechanical parameters evaluated ex vivo and vertebral deformity status in vivo. We propose to evaluate the above hypotheses by addressing the following specific aims: 1. We will validate the proposed method in specimens of the distal tibia and radius by performing mechanical testing and comparing the data with ?FE-derived estimates of elastic moduli derived from micro-CT and ?MR images as well as with those from vertebral bone of the same donors. 2. We will evaluate a cohort of postmenopausal women with a protocol consisting of acquisition of high- resolution 3D ?MRI of the distal tibia and radius, 3D BMD by pQCT at matching anatomic locations, MRI of the spine for vertebral deformity assessment, and DXA aBMD at the spine and hip. 3. We will derive structural and mechanical parameters at the two peripheral sites to test the above hypotheses by comparing ?FE-estimated parameters with measures of structure and BMD, and with vertebral deformity status. The proposed in vivo MRI study will provide new insight into the microstructural and mechanical implications of osteoporosis, thereby providing the basis for translation of the methodology to the clinic, which is the long-term objective underlying the project. PUBLIC HEALTH RELEVANCE: The relationship between measures of bone strength and architecture is not understood and only recently technology has become available in the form of high-resolution noninvasive imaging and micro-finite-element analysis to explore these associations. In this project we address the hypothesis that bone mechanical competence can be predicted on the basis of high-resolution MRI in human cadaver specimens comparing mechanical test results with computational biomechanics and apply the methodology to postmenopausal women at risk of fracture by comparing the structural and mechanical parameters with vertebral deformity status.